Cadherin-mediated interactions between epithelial cells contribute to the maintenance of mucosal barriers that prevent access of environmental agents such as pathogens and allergens to underlying tissue and immunocytes. Several observations suggest a link between epithelial cadherin dysregulation, barrier disruption, and allergic disease. For example, reduced E-cadherin (CDH1) protein in asthmatic patients is associated with decreased airway epithelial barrier function (Trautmann et al., Apoptosis and loss of adhesion of bronchial epithelial cells in asthma. Int Arch Allergy Immunol. 2005; 138(2):142-50; de Boer W et al., Altered expression of epithelial junctional proteins in atopic asthma: possible role in inflammation. Can J Physiol Pharmacol. 2008; 86(3):105-12), and levels of membrane-localized CDH1 are decreased in the lesional skin of atopic dermatitis patients (Trautmann et al. The differential fate of cadherins during T-cell-induced keratinocyte apoptosis leads to spongiosis in eczematous dermatitis. J Invest Dermatol. 2001; 117(4):927-34). In addition to affecting barrier function, inhibition of CDH1 expression in vitro results in increased expression of the chemoattractant cytokine CCL17 by human bronchial epithelial cells (Heij ink I H, et al. Down-regulation of E-cadherin in human bronchial epithelial cells leads to epidermal growth factor receptor-dependent Th2 cell-promoting activity. J Immunol. 2007; 178(12):7678-85). Whether other cadherins influence allergic disease through impacting epithelial barrier maintenance or gene expression is not known.
In addition to homotypic interaction of cadherin molecules expressed by adjacent epithelial cells, cadherin-mediated interactions occur between epithelial cells and leukocytes. For example, CDH1 expressed by epithelial cells can bind CDH1 expressed by leukocytes or heterotypic molecules expressed by leukocytes such as integrins, in both cases influencing biological outcomes. However, reports of such epithelial cadherin/leukocyte integrin interactions are rare and to our knowledge limited to the observation that CDH1 binds lymphocyte integrin αEβ7 and regulates the activation and localization of epidermal and intestinal intraepithelial lymphocytes (Cepek K L et al., Integrin alpha E beta 7 mediates adhesion of T lymphocytes to epithelial cells. J Immunol. 1993; 150(8 Pt 1):3459-70; Cepek K L et al., Adhesion between epithelial cells and T lymphocytes mediated by E-cadherin and the alpha E beta 7 integrin. Nature. 1994; 372(6502):190-3; Schon et al. Mucosal T lymphocyte numbers are selectively reduced in integrin alpha E (CD103)-deficient mice. J Immunol. 1999; 162(11):6641-9; Uchida et al. Role for E-cadherin as an inhibitory receptor on epidermal gammadelta T cells. J Immunol. 2011; 186(12):6945-54). Despite these observations regarding CDH1, the involvement of other cadherins in the regulation of immunologic processes mediated by the mucosal epithelium such as their binding to integrins has not been described.
A central feature of chronic allergic inflammation is T helper cell type 2 (Th2)-driven eosinophil accumulation typically mediated by an IL-13-driven cascade that elicits eosinophil trafficking from the blood to the tissue. This process involves the coordinate expression and activation of eosinophil-expressed selectins and integrins and their counter-receptors on activated endothelium, as well as the induction of eosinophil-activating chemokines such as the eotaxins (Broide D, and Sriramarao P. Eosinophil trafficking to sites of allergic inflammation. Immunological reviews. 2001; 179 163-72; Tachimoto et al. Cross-talk between integrins and chemokines that influences eosinophil adhesion and migration. Int Arch Allergy Immunol. 2002; 128 Suppl 1 18-20; Rosenberg et al. Eosinophil trafficking in allergy and asthma. J Allergy Clin Immunol. 2007; 119(6):1303-10; quiz 11-2; Bochner B S. Road signs guiding leukocytes along the inflammation superhighway. J Allergy Clin Immunol. 2000; 106(5):817-28). While the mechanism of eosinophil transendothelial migration is well described, the processes involved in eosinophil transepithelial migration are not understood as completely. Moreover, much remains to be learned regarding the integrin/counter-receptor interactions occurring between epithelial cells and leukocytes and their consequences in the context of allergic inflammation.
The present inventors identified a previously uncharacterized cadherin, CDH26, that was markedly overexpressed in human gastrointestinal tissue with active eosinophilic inflammation. No studies of this molecule have been reported, although its transcript appears to be upregulated in epithelial cells under Th2-associated conditions (Woodruff et al. Genome-wide profiling identifies epithelial cell genes associated with asthma and with treatment response to corticosteroids. Proc Natl Acad Sci USA. 2007; 104(40):15858-63; Shum et al. The adipocyte fatty acid-binding protein aP2 is required in allergic airway inflammation. J Clin Invest. 2006; 116(8):2183-92; Zhen et al. IL-13 and epidermal growth factor receptor have critical but distinct roles in epithelial cell mucin production. Am J Respir Cell Mol Biol. 2007; 36(2):244-53; Li R W, and Gasbarre L C. A temporal shift in regulatory networks and pathways in the bovine small intestine during Cooperia oncophora infection. Int J Parasitol. 2009; 39(7):813-24).